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Published on: September 17, 2017
Rapid protein-ligand costructures using chemical shift perturbations
1Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA.
Journal of the American Chemical Society
|December 20, 2007
Summary
This study introduces a faster method for determining protein-ligand structures using NMR chemical shift perturbation (CSP) data. This approach improves molecular docking accuracy in structure-based drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Chemistry
Background:
- Structure-based drug discovery relies on accurate protein-ligand complex structures.
- Traditional methods like X-ray crystallography and NMR are time-consuming.
- Molecular docking aids efficiency but faces challenges with accuracy and ligand conformation.
Purpose of the Study:
- To develop a rapid and accurate method for determining protein-ligand costructures.
- To enhance the efficiency and reliability of structure-based drug design.
- To integrate NMR chemical shift perturbation (CSP) data with molecular docking.
Main Methods:
- Utilized 2D 1H-15N HSQC spectra for NMR chemical shift perturbation (CSP) data acquisition.
- Developed the AutoDockFilter program to guide and filter AutoDock calculations using CSP data.
- Validated the method on 19 distinct protein-ligand complexes.
Main Results:
- The novel method rapidly determines accurate protein-ligand costructures.
- Docked conformers showed an average RMSD of 1.17 +/- 0.74 Å compared to X-ray structures.
- Demonstrated successful application across multiple protein-ligand systems.
Conclusions:
- NMR CSP data offers a viable approach to accelerate structure-based drug design.
- The AutoDockFilter program effectively improves the accuracy of molecular docking.
- This integrated method enhances throughput and reliability in drug discovery.
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